EP0884319B1 - N- (1-nButyl-4-piperidyl)methyl -3,4-dihydro-2H- 1,3 oxazino 3,2-a indol-10-carboxamid oder ein pharmazeutisch annehmbares Salz davon - Google Patents

N- (1-nButyl-4-piperidyl)methyl -3,4-dihydro-2H- 1,3 oxazino 3,2-a indol-10-carboxamid oder ein pharmazeutisch annehmbares Salz davon Download PDF

Info

Publication number
EP0884319B1
EP0884319B1 EP98114130A EP98114130A EP0884319B1 EP 0884319 B1 EP0884319 B1 EP 0884319B1 EP 98114130 A EP98114130 A EP 98114130A EP 98114130 A EP98114130 A EP 98114130A EP 0884319 B1 EP0884319 B1 EP 0884319B1
Authority
EP
European Patent Office
Prior art keywords
indole
pharmaceutically acceptable
piperidyl
methyl
carboxamide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP98114130A
Other languages
English (en)
French (fr)
Other versions
EP0884319A3 (de
EP0884319A2 (de
Inventor
Laramie Mary GlaxoSmithKline GASTER
Paul Adrian GlaxoSmithKline Wyman
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Ltd
Original Assignee
SmithKline Beecham Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB929205428A external-priority patent/GB9205428D0/en
Priority claimed from GB929218846A external-priority patent/GB9218846D0/en
Priority claimed from GB929227045A external-priority patent/GB9227045D0/en
Application filed by SmithKline Beecham Ltd filed Critical SmithKline Beecham Ltd
Publication of EP0884319A2 publication Critical patent/EP0884319A2/de
Publication of EP0884319A3 publication Critical patent/EP0884319A3/de
Application granted granted Critical
Publication of EP0884319B1 publication Critical patent/EP0884319B1/de
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • A61K31/245—Amino benzoic acid types, e.g. procaine, novocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4453—Non condensed piperidines, e.g. piperocaine only substituted in position 1, e.g. propipocaine, diperodon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/452—Piperidinium derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • This invention relates to a novel compound having pharmacological activity, to a process for its preparation and to its use as a pharmaceutical.
  • EP-A-429984 (Nisshin Flour Milling Co., Ltd.) describes indole derivatives having 5-HT 3 receptor antagonist activity.
  • WO 91/16045 (SmithKline and French Laboratories Limited) describes the use of cardiac 5-HT 4 receptor antagonists in the treatment of atrial arrhythmias and stroke.
  • EP-A-501322 (Glaxo Group Limited) describes indole derivatives having 5-HT 4 antagonist activity.
  • a novel, structurally distinct compound has now been discovered, which compound is an indole derivative 1,2-disubstituted by alkyleneoxy, with an azacyclic moiety. This compound has 5-HT 4 receptor antagonist activity.
  • the present invention provides N-[(1- n butyl-4-piperidyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamide, namely the compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein
  • the pharmaceutically acceptable salts of the compound of the formula (I) include acid addition salts with conventional acids such as hydrochloric, hydrobromic, boric, phosphoric, sulphuric acids and pharmaceutically acceptable organic acids such as acetic, tartaric, maleic, citric, succinic, benzoic, ascorbic, methanesulphonic, ⁇ -keto glutaric, ⁇ -glycerophosphoric, and glucose-1-phosphoric acids.
  • conventional acids such as hydrochloric, hydrobromic, boric, phosphoric, sulphuric acids
  • pharmaceutically acceptable organic acids such as acetic, tartaric, maleic, citric, succinic, benzoic, ascorbic, methanesulphonic, ⁇ -keto glutaric, ⁇ -glycerophosphoric, and glucose-1-phosphoric acids.
  • Examples of pharmaceutically acceptable salts include quaternary derivatives of the compound of formula (I) which are the compound quaternised by compounds R x -T wherein R x is methyl, ethyl, n -propyl, iso -propyl, benzyl or phenethyl, and T is a radical corresponding to an anion of an acid.
  • Suitable examples of T include halide such as chloride, bromide and iodide.
  • Examples of pharmaceutically acceptable salts also include internal salts which are N-oxides.
  • the compound of the formula (I), and its pharmaceutically acceptable salts, may also form pharmaceutically acceptable solvates, such as hydrates, which are included wherever the compound of formula (I) or a salt thereof is herein referred to.
  • the compound of formula (I) may be prepared by conventional coupling of the indole moiety with Z. Suitable methods are as described in GB 2125398A (Sandoz Limited), GB 1593146A and EP-A-36269 (Beecham Group p.l.c.), EP-A-429984 (Nisshin Flour Milling Co.) and EP-A-328200 (Merck Sharp & Dohme Limited). Reference is also made to EP-A-501322 (Glaxo Group Limited). It will be appreciated that the (CH 2 ) r -O containing ring or R 3 /R 4 introduction/modification may be carried out before or after coupling.
  • Aza(bi)cyclic side chain intermediates are known compounds or may be prepared according to the methods described in PCT/GB92/01519 and /01612 (SmithKline Beecham p.l.c.).
  • the compounds of the present invention are 5-HT 4 receptor antagonists and it is thus believed may generally be used in the treatment or prophylaxis of gastrointestinal disorders, cardiovascular disorders and CNS disorders.
  • IBS irritable bowel syndrome
  • these compounds block the ability of 5-HT to stimulate gut motility via activation of enteric neurones. In animal models of IBS, this can be conveniently measured as a reduction of the rate of defaecation. They are also of potential use in the treatment of urinary incontinence which is often associated with IBS.
  • They may also be of potential use in other gastrointestinal disorders, such as those associated with upper gut motility, and as antiemetics.
  • they are of potential use in the treatment of the nausea and gastric symptoms of gastro-oesophageal reflux disease and dyspepsia.
  • Antiemetic activity is determined in known animal models of cytotoxic-agent/radiation induced emesis.
  • platelet-derived 5-HT induces atrial arrhythmias which encourage atrial fibrillation and atrial disorders are associated with symptomatic cerebral and sytemic embolism.
  • Cerebral embolism is the most common cause of ischaemic stroke and the heart the most common source of embolic material. Of particular concern is the frequency of embolism associated with atrial fibrillation.
  • Anxiolytic activity is likely to be effected via the hippocampus (Dumuis et al 1988, Mol Pharmacol., 34, 880-887). Activity may be demonstrated in standard animal models, the social interaction test and the X-maze test.
  • Migraine sufferers often undergo situations of anxiety and emotional stress that precede the appearance of headache (Sachs, 1985, Migraine, Pan Books, London). It has also been observed that during and within 48 hours of a migraine attack, cyclic AMP levels are considerably increased in the cerebrospinal fluid (Welch et al ., 1976, Headache 16, 160-167). It is believed that a migraine, including the prodomal phase and the associated increased levels of cyclic AMP are related to stimulation of 5-HT 4 receptors, and hence that administration of a 5-HT 4 antagonist is of potential benefit in relieving a migraine attack.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • compositions are prepared by admixture and are usually adapted for enteral such as oral, nasal or rectal, or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, nasal sprays, suppositories, injectable and infusable solutions or suspensions. Sublingual or transdermal administration is also envisaged. Orally administrable compositions are preferred, since they are more convenient for general use.
  • Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, flavourings, and wetting agents.
  • the tablets may be coated according to well known methods in the art, for example with an enteric coating.
  • Suitable fillers for use include cellulose, mannitol, lactose and other similar agents.
  • Suitable disintegrants include starch, polyvinylpolypyrrolidone and starch derivatives such as sodium starch glycollate.
  • Suitable lubricants include, for example, magnesium stearate.
  • Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or
  • Oral liquid preparations are usually in the form of aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs or are presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and flavouring or colouring agents.
  • the oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art.
  • fluid unit dose forms are prepared containing a compound of the present invention and a sterile vehicle.
  • the compound depending on the vehicle and the concentration, can be either suspended or dissolved.
  • Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by exposure of ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound of the invention.
  • the invention further provides the use of the compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier in the preparation by admixture of a pharmaceutical composition for the treatment of irritable bowel syndrome, gastro-oesophagal reflux disease, dyspepsia, atrial arrhythmias and stroke, anxiety and/or migraine in mammals, such as humans, the composition being for the administration of an effective amount of the compound of the formula (I) or the pharmaceutically acceptable salt thereof.
  • the composition is for treatment of IBS or atrial arrhythmias and stroke.
  • a unit dose for a 70 kg adult will normally contain 0.05 to 1000 mg for example 0.5 to 500 mg, of the compound of the invention.
  • Unit doses may be administered once or more than once a day, for example, 2, 3 or 4 times a day, more usually 1 to 3 times a day, that is in the range of approximately 0.0001 to 50 mg/kg/day, more usually 0.0002 to 25 mg/kg/day.
  • the invention also provides the compound of formula (I) or a pharmaceutically acceptable salt thereof for use as an active therapeutic substance, in particular for use as a 5-HT 4 receptor antagonist in the treatment of the disorders hereinbefore described.
  • the invention also provides the use of the compound of formula (I) in the manufacture of a medicament for use as a 5-HT 4 receptor antagonist in the treatment of the disorders hereinbefore described.
  • Method 1 A stirred solution of N-chlorosuccinimide (57 mg, 0.48 mmole) in chloroform (3 ml) was treated with a solution of N-[(1- n butyl-4-piperidyl)methyl] indole-3-carboxamide (100 mg, 0.32 mmole) in chloroform (8 ml) and kept at room temperature for 2h, then treated with 3-bromo-1-propanol (0.03 ml, 0.32 mmole). After stirring for 16h, more 3-bromo-1-propanol (0.03 ml, 0.32 mmole) was added.
  • the mixture was stirred at room temperature for a further 3h, then treated with excess 10% Na 2 CO 3 solution and extracted with chloroform.
  • the extract was dried (Na 2 SO 4 ) and concentrated in vacuo to leave a yellow oil, which was dissolved in acetone (10 ml), treated with anhydrous potassium carbonate (130 mg, 0.96 mmole) and stirred at room temperature for 16h.
  • the mixture was concentrated in vacuo , the residue treated with 10% Na 2 CO 3 solution (10 ml) and extracted with chloroform.
  • Method 2 A stirred suspension of N-[(1- n butyl-4-piperidyl)methyl] indole-3-carboxamide (120g, 0.38 mole) in chloroform (2 L) under nitrogen at room temperature was treated with freshly distilled 3-bromo-1-propanol (69 ml, 0.77 mole) followed by the portionwise addition of dry N-chlorosuccinimide (55g, 0.42 mole) over 5 minutes. The resulting yellow solution was stirred for 2.5h, then treated with 1M HCl in ether (15 ml, 0.015 mole). A moderate exotherm occurred and the reaction colour changed to orange.
  • guinea-pigs Male guinea-pigs, weighing 250-400g are used. Longitudinal muscle-myenteric plexus preparations, approximately 3cm long, are obtained from the distal colon region. These are suspended under a 0.5g load in isolated tissue baths containing Krebs solution bubbled with 5% CO 2 in O 2 and maintained at 37°C. In all experiments, the Krebs solution also contains methiothepin 10 -7 M and granisetron 10 -6 M to block effects at 5-HT 1 , 5-HT 2 and 5-HT 3 receptors.
  • a concentration of 5-HT is selected so as to obtain a contraction of the muscle approximately 40-70% maximum(10 -9 M approx).
  • the tissue is then alternately dosed every 15min with this concentration of 5-HT and then with an approximately equi-effective concentration of the nicotine receptor stimulant, dimethylphenylpiperazinium (DMPP).
  • DMPP dimethylphenylpiperazinium
  • increasing concentrations of a putative 5-HT 4 receptor antagonist are then added to the bathing solution.
  • the effects of this compound are then determined as a percentage reduction of the contractions evoked by 5-HT or by DMPP. From this data, pIC 50 values are determined, being defined as the -log concentration of antagonist which reduces the contraction by 50%.
  • a compound which reduces the response to 5-HT but not to DMPP is believed to act as a 5-HT 4 receptor antagonist.
  • the compound was tested in the piglet spontaneous beating screen (Naunyn-Schmiedeberg's Arch. Pharmacol 342, 619-622).
  • pK B (-log 10 K B ) value for the compound of the Example was 10.05.
  • Rat oesophageal tunica muscularis mucosae is set up according to Baxter et. al . Naunyn-Schmiedeberg's Arch. Pharmacol., 343, 439-446 (1991).
  • the inner smooth muscle tube of the muscularis mucosae is isolated and mounted for isometric tension recording in oxygenated (95% O 2 /5% CO 2 ) Tyrodes solution at 37°C. All experiments are performed in pargyline pre-treated preparations (100 ⁇ M for 15 min followed by washout) and in the presence of cocaine (30 ⁇ M). Relaxant responses to 5-HT are obtained after pre-contracting the oesophagus tissue with carbachol (3 ⁇ M).
  • the compound is tested for inhibition in the in vivo method described in "Stimulation of canine motility by BRL 24924, a new gastric prokinetic agent", Bermudez et al , J. Gastrointestinal Motility, 1990, 2(4), 281-286.
  • the box is made of white perspex 54 cm x 37 cm x 26 cm with a transparent perspex front side and no lid.
  • the floor is divided up into 24 squares and the box is brightly lit (115 lux).
  • Active social interactive behaviours (grooming, sniffing, climbing over or under, following, biting, mounting and boxing) are scored blind for the next 15 min by remote video monitoring to give total interaction scores.
  • the number of squares crossed by each rat is also scored and summed. After the end of each test the box is carefully wiped.
  • the compound of the Example increased total interaction scores over the dose range 0.01 10 mg/kg p.o.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Cardiology (AREA)
  • Neurosurgery (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Indole Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Claims (26)

  1. N-[(1-nButyl-4-piperidyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indol-10-carboxamid oder ein pharmazeutisch verträgliches Salz davon.
  2. N-[(1-nButyl-4-piperidyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indol-10-carboxamid.
  3. Pharmazeutisch verträgliches Salz gemäß Anspruch 1, welches ein Säureadditionssalz mit Chlorwasserstoffsäure, Bromwasserstoffsäure, Borsäure, Phosphorsäure oder Schwefelsäure oder mit einer pharmazeutisch verträglichen organischen Säure ist.
  4. Pharmazeutisch verträgliches Salz gemäß Anspruch 1, welches ein Säureadditionssalz mit Chlorwasserstoffsäure, Bromwasserstoffsäure, Borsäure, Phosphorsäure, Schwefelsäure, Essigsäure, Weinsäure, Maleinsäure, Zitronensäure, Bernsteinsäure, Benzoesäure, Ascorbinsäure, Methansulfonsäure, α-Ketoglutarsäure, α-Glycerophosphorsäure oder Glucose-1-phosphorsäure ist.
  5. Hydrochloridsalz von N-[(1-nButyl-4-piperidyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indol-10-carboxamid.
  6. Arzneimittel, umfassend N-[(1-nButyl-4-piperidyl)methyl]-3,4-dihydro-2H-[1,3]-oxazino[3,2-a]indol-10-carboxamid oder ein pharmazeutisch verträgliches Salz davon gemäß einem der Ansprüche 1 bis 5, und einen pharmazeutisch verträglichen Träger.
  7. Arzneimittel gemäß Anspruch 6, welches eine Einheitsdosis für einen 70 kg schweren Erwachsenen ist, welches 0,05 bis 1000 mg einer Verbindung gemäß einem der Ansprüche 1 bis 5 enthält.
  8. Arzneimittel gemäß Anspruch 7, welches eine Einheitsdosis für einen 70 kg schweren Erwachsenen ist, welches 0,5 bis 500 mg einer Verbindung gemäß einem der Ansprüche 1 bis 5 enthält.
  9. Arzneimittel gemäß einem der Ansprüche 6, 7 oder 8, welches durch Beimischen hergestellt und für die orale Verabreichung geeignet ist.
  10. Arzneimittel gemäß Anspruch 9 in Tabletten- oder Kapselform.
  11. N-[(1-nButyl-4-piperidyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indol-10-carboxamid oder ein pharmazeutisch verträgliches Salz davon gemäß einem der Ansprüche 1 bis 5 zur Verwendung als eine therapeutisch wirksame Substanz.
  12. N-[(1-nButyl-4-piperidyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indol-10-carboxamid oder ein pharmazeutisch verträgliches Salz davon gemäß Anspruch 11 zur Verwendung als ein 5-HT4-Rezeptorantagonist bei der Behandlung von Reizkolon, Gastro-Ösophagus-Refluxerkrankung, Dyspepsie, Vorhofarrhythmie und Schlaganfall, Angst und/oder Migräne bei Säugern.
  13. N-[(1-nButyl-4-piperidyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indol-10-carboxamid oder ein pharmazeutisch verträgliches Salz davon gemäß Anspruch 11 zur Verwendung als ein 5-HT4-Rezeptorantagonist bei der Behandlung von Vorhofarrhythmie und Schlaganfall bei Säugern.
  14. N-[(1-nButyl-4-piperidyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indol-10-carboxamid oder ein pharmazeutisch verträgliches Salz davon gemäß Anspruch 11 zur Verwendung als ein 5-HT4-Rezeptorantagonist bei der Behandlung von Vorhofarrhythmie und Schlaganfall bei Menschen.
  15. N-[(1-nButyl-4-piperidyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indol-10-carboxamid oder ein pharmazeutisch verträgliches Salz davon gemäß Anspruch 11 zur Verwendung als ein 5-HT4-Rezeptorantagonist bei der Behandlung von Harninkontinenz.
  16. Verwendung von N-[(1-nButyl-4-piperidyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indol-10-carboxamid zur Herstellung eines Medikaments zur Verwendung als ein 5-HT4-Rezeptorantagonist bei der Behandlung oder Vorbeugung von Gastrointestinal-Störungen, Herzkreislauf-Störungen und ZNS-Störungen.
  17. Verwendung von N-[(1-nButyl-4-piperidyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indol-10-carboxamid zur Herstellung eines Medikaments zur Verwendung als ein 5-HT4-Rezeptorantagonist bei der Behandlung von Reizkolon, Gastro-Ösophagus-Refluxerkrankung, Dyspepsie, Vorhofarrhythmie und Schlaganfall, Angst und/oder Migräne bei Säugern.
  18. Verwendung von N-[(1-nButyl-4-piperidyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indol-10-carboxamid oder eines pharmazeutisch verträglichen Salzes davon, wie in einem der Ansprüche 1 bis 5 definiert, und eines pharmazeutisch verträglichen Trägers bei der Herstellung durch Beimischen eines Arzneimittels wie in Anspruch 6 definiert, wobei das Arzneimittel zur Behandlung von Reizkolon, Gastro-Ösophagus-Refluxerkrankung, Dyspepsie, Vorhofarrhythmie und Schlaganfall, Angst und/oder Migräne bei Säugern bestimmt ist und wobei das Arzneimittel zur Verabreichung einer wirksamen Menge des N-[(1-nButyl-4-piperidyl)methyl]-3,4-dihydro-2H-[1,3]-oxazino[3,2-a]indol-10-carboxamids oder des pharmazeutisch verträglichen Salzes davon bestimmt ist.
  19. Verwendung gemäß Anspruch 18, wobei das Arzneimittel eine Einheitsdosis für einen 70 kg schweren Erwachsenen ist, welche 0,5 bis 500 mg einer Verbindung gemäß einem der Ansprüche 1 bis 5 enthält.
  20. Verwendung gemäß Anspruch 18 oder 19, wobei das Arzneimittel eine Einheitsdosis zur Verabreichung 1 bis 3 Mal täglich im Bereich von 0,0002 bis 25 mg/kg/Tag ist.
  21. Verwendung gemäß Anspruch 18, 19 oder 20, wobei das Arzneimittel für die orale Verabreichung geeignet ist.
  22. Verwendung gemäß Anspruch 21, wobei das Arzneimittel in Tabletten- oder Kapselform vorliegt.
  23. Verwendung gemäß Anspruch 17, 18, 19, 20, 21 oder 22, wobei das Medikament oder das Arzneimittel zur Behandlung von Vorhofarrhythmie und Schlaganfall bei Säugern bestimmt ist.
  24. Verwendung gemäß Anspruch 17, 18, 19, 20, 21 oder 22, wobei das Medikament oder das Arzneimittel zur Behandlung von Vorhofarrhythmie und Schlaganfall bei Menschen bestimmt ist.
  25. Verwendung gemäß Anspruch 17, 18, 19, 20, 21 oder 22, wobei das Medikament oder das Arzneimittel zur Behandlung von Reizkolon bei Menschen bestimmt ist.
  26. Verwendung von N-[(1-nButyl-4-piperidyl)methyl]-3,4-dihydro-2H-[1,3]oxazino [3,2-a]indol-10-carboxamid zur Herstellung eines Medikaments zur Verwendung als ein 5-HT4-Rezeptorantagonist bei der Behandlung von Harninkontinenz.
EP98114130A 1992-03-12 1993-03-10 N- (1-nButyl-4-piperidyl)methyl -3,4-dihydro-2H- 1,3 oxazino 3,2-a indol-10-carboxamid oder ein pharmazeutisch annehmbares Salz davon Expired - Lifetime EP0884319B1 (de)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
GB9205428 1992-03-12
GB929205428A GB9205428D0 (en) 1992-03-12 1992-03-12 Pharmaceuticals
GB929218846A GB9218846D0 (en) 1992-09-05 1992-09-05 Pharmaceuticals
GB9218846 1992-09-05
GB9227045 1992-12-29
GB929227045A GB9227045D0 (en) 1992-12-29 1992-12-29 Pharmaceuticals
EP93905561A EP0630376B1 (de) 1992-03-12 1993-03-10 Kondensierte indol-derivate als 5-ht4-rezeptor-antagonisten

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
EP93905561A Division EP0630376B1 (de) 1992-03-12 1993-03-10 Kondensierte indol-derivate als 5-ht4-rezeptor-antagonisten

Publications (3)

Publication Number Publication Date
EP0884319A2 EP0884319A2 (de) 1998-12-16
EP0884319A3 EP0884319A3 (de) 1999-02-10
EP0884319B1 true EP0884319B1 (de) 2004-05-06

Family

ID=27266092

Family Applications (2)

Application Number Title Priority Date Filing Date
EP93905561A Expired - Lifetime EP0630376B1 (de) 1992-03-12 1993-03-10 Kondensierte indol-derivate als 5-ht4-rezeptor-antagonisten
EP98114130A Expired - Lifetime EP0884319B1 (de) 1992-03-12 1993-03-10 N- (1-nButyl-4-piperidyl)methyl -3,4-dihydro-2H- 1,3 oxazino 3,2-a indol-10-carboxamid oder ein pharmazeutisch annehmbares Salz davon

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP93905561A Expired - Lifetime EP0630376B1 (de) 1992-03-12 1993-03-10 Kondensierte indol-derivate als 5-ht4-rezeptor-antagonisten

Country Status (29)

Country Link
EP (2) EP0630376B1 (de)
JP (1) JP2831467B2 (de)
KR (1) KR100282730B1 (de)
CN (2) CN1043893C (de)
AP (1) AP401A (de)
AT (2) ATE180785T1 (de)
AU (1) AU671102B2 (de)
CA (1) CA2131797C (de)
CY (1) CY2510B1 (de)
CZ (1) CZ286194B6 (de)
DE (2) DE69333504T2 (de)
DK (2) DK0884319T3 (de)
ES (2) ES2219813T3 (de)
FI (1) FI107158B (de)
GR (1) GR3030668T3 (de)
HU (1) HU219121B (de)
IL (1) IL105003A (de)
MA (1) MA22819A1 (de)
MX (1) MX9301348A (de)
MY (1) MY110110A (de)
NO (1) NO303638B1 (de)
NZ (1) NZ249565A (de)
PT (1) PT884319E (de)
RU (1) RU2104279C1 (de)
SG (1) SG50693A1 (de)
SI (1) SI9300114B (de)
SK (1) SK281423B6 (de)
UA (1) UA41311C2 (de)
WO (1) WO1993018036A1 (de)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8232285B2 (en) 2007-06-22 2012-07-31 Arqule, Inc. Quinazolinone compounds and methods of use thereof

Families Citing this family (49)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5998409A (en) * 1992-03-12 1999-12-07 Smithkline Beecham Plc Condensed indole derivatives as 5HT4 -receptor antagonists
GB9316195D0 (en) * 1993-08-05 1993-09-22 Smithkline Beecham Plc Pharmaceuticals
US5852014A (en) * 1992-03-12 1998-12-22 Smithkline Beecham P.L.C. Condensed indole derivatives as 5HT4 -receptor antagonists
MX9305947A (es) * 1992-09-29 1994-06-30 Smithkline Beecham Plc Compuestos antagonistas del receptor 5-ht4, procedimiento para su preparacion y composiciones farmaceuticas que las contienen.
US5726187A (en) * 1992-10-16 1998-03-10 Smithkline Beecham Plc N-alkylpiperidinyl-4-methyl carboxylic esters/amides of condensed ring systems as 5-HT4 receptor antagonists
NZ257545A (en) * 1992-11-05 1997-01-29 Smithkline Beecham Plc Heterocyclic (especially piperidine) derivatives and pharmaceutical compositions
FR2699921B1 (fr) * 1992-12-30 1995-02-10 Synthelabo Dérivés d'acide 2-(thien-2-yl)imidazo[2,1-b]benzothiazole-3-acétique, leur préparation et leur application en thérapeutique.
GB9303340D0 (en) * 1993-02-19 1993-04-07 Smithkline Beecham Plc Pharmaceuticals
GB9310582D0 (en) * 1993-05-22 1993-07-07 Smithkline Beecham Plc Pharmaceuticals
GB9312348D0 (en) * 1993-06-16 1993-07-28 Smithkline Beecham Plc Pharmaceuticals
KR100219922B1 (ko) * 1996-05-16 1999-09-01 이서봉 신규한 항바이러스성 6-아릴옥시 및 6-아릴카르보닐 2,4-피리미딘디온 유도체 및 그의 제조 방법
US6013666A (en) * 1996-07-02 2000-01-11 Sang Sup Jew Oxirane carboxylic acid derivative and its manufacturing method
JP3911297B2 (ja) * 1996-08-16 2007-05-09 スミスクライン・ビーチャム・パブリック・リミテッド・カンパニー Ｎ―［（１―ｎブチル―４―ピペリジル）メチル］―３，４―ジヒドロ―２Ｈ―［１，３］オキサジノ［３，２―ａ］インドール―１０―カルボキシアミドおよび塩ならびに製造における中間体
US6100397A (en) * 1996-08-16 2000-08-08 Smithkline Beecham Plc Process for the preparation of N-[(1-n butyl-4-piperidyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a] indole-10-carboxamide and salts and intermediates in the process
GB9618967D0 (en) * 1996-09-11 1996-10-23 Smithkline Beecham Plc Pharmaceuticals
GB9725933D0 (en) * 1997-12-05 1998-02-04 Smithkline Beecham Plc Pharmaceuticals
US6277870B1 (en) * 1998-05-04 2001-08-21 Astra Ab Use
US6251893B1 (en) * 1998-06-15 2001-06-26 Nps Allelix Corp. Bicyclic piperidine and piperazine compounds having 5-HT6 receptor affinity
US20020091271A1 (en) 1998-07-16 2002-07-11 Smithkline Beecham Plc Process for the preparation of an indole derivative
GB9819035D0 (en) 1998-09-01 1998-10-28 Cerebrus Res Ltd Chemical compounds VII
AU758807B2 (en) * 1998-09-10 2003-03-27 F. Hoffmann-La Roche Ag Dihydrobenzodioxine carboxamide and ketone derivatives as 5-HT4 receptor antagonists
GB9820294D0 (en) * 1998-09-17 1998-11-11 Smithkline Beecham Plc Pharmaceuticals
US7230000B1 (en) 1999-10-27 2007-06-12 Cytokinetics, Incorporated Methods and compositions utilizing quinazolinones
US6545004B1 (en) 1999-10-27 2003-04-08 Cytokinetics, Inc. Methods and compositions utilizing quinazolinones
IL154279A0 (en) * 2000-08-07 2003-09-17 Glaxosmithkline Lab Sas Use of 5ht4 receptor antagonists in the manufacture of a medicament for the prophylaxis or treatment of atrial fibrillation
AU2005203196B9 (en) * 2000-08-07 2009-04-09 Glaxo Group Limited The use of 5HT4 receptor antagonists in the prophylaxis or treatment of certain cardiovascular conditions
AU782870C (en) * 2000-08-07 2007-03-15 Glaxo Group Limited The use of 5HT4 receptor antagonists in the prophylaxis or treatment of certain cardiovascular conditions
AU782863C (en) * 2000-08-07 2006-08-31 Glaxo Group Limited The use of 5HT4 receptor antagonists in the prophylaxis or treatment of certain cardiovascular conditions
NZ535261A (en) * 2000-08-08 2004-12-24 Smithkline Beecham P A tablet comprising the hydrochloride salt of N-(1-nbutyl-4-piperidinyl)methyl]-3,4-[1,3]oxazino[3,2-a] indole-10-carboxamide
AU7655801A (en) * 2000-08-08 2002-02-18 Smithkline Beecham Plc Pharmaceutical composition comprising condensed indole compound
JP2005523276A (ja) * 2002-02-14 2005-08-04 グラクソ　グループ　リミテッド Ｎ−［（１−ｎ−ブチル−４−ピペリジニル）メチル］−３，４−ジヒドロ−２ｈ−［１，３］オキサジノ［３，２−ａ］インドール−１０−カルボキシアミド（ｓｂ２０７２６６）またはその塩および乾燥造粒操作を含む方法
WO2003070701A2 (en) 2002-02-15 2003-08-28 Cytokinetics, Inc. Syntheses of quinazolinones
CA2485148A1 (en) 2002-05-09 2003-11-20 Cytokinetics, Inc. Pyrimidinone compounds, compositions and methods
US7214800B2 (en) 2002-05-09 2007-05-08 Cytokinetics, Inc. Compounds, compositions, and methods
GB0211230D0 (en) 2002-05-16 2002-06-26 Medinnova Sf Treatment of heart failure
EP1513820A4 (de) 2002-05-23 2006-09-13 Cytokinetics Inc Verbindungen, zusammensetzungen und verfahren
WO2003106426A1 (en) 2002-06-14 2003-12-24 Cytokinetics, Inc. Compounds, compositions, and methods
AU2003256805A1 (en) 2002-07-23 2004-02-09 Cytokinetics, Inc. Compounds compositions and methods
WO2004034972A2 (en) 2002-09-30 2004-04-29 Cytokinetics, Inc. Compounds, compositions, and methods
ITMI20031468A1 (it) 2003-07-18 2005-01-19 Acraf Farmaco ativo nel dolore neuropatico
ITMI20031467A1 (it) * 2003-07-18 2005-01-19 Acraf Farmaco attivo nel dolore neuropatico
EP1692112A4 (de) 2003-12-08 2008-09-24 Cytokinetics Inc Verbindungen, zusammensetzungen und verfahren
JP4740152B2 (ja) 2003-12-23 2011-08-03 セロドス アクスイェ セルスカブ 末梢性５−ｈｔ受容体の修飾因子
JP4612301B2 (ja) * 2003-12-26 2011-01-12 広栄化学工業株式会社 １−アルキル−４−アミノメチルピペリジンの製造法
EP1824820A2 (de) * 2004-12-07 2007-08-29 Janssen Pharmaceutica N.V. Substituierte derivate von tetracyclischem tetrahydrofuran, pyrrolidin und tetrahydrothiopen
RU2320662C1 (ru) * 2006-08-24 2008-03-27 Андрей Александрович Иващенко ЗАМЕЩЕННЫЕ ПИРРОЛО[4,3-b]ИНДОЛЫ, КОМБИНАТОРНАЯ И ФОКУСИРОВАННАЯ БИБЛИОТЕКИ, ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ, СПОСОБЫ ИХ ПОЛУЧЕНИЯ И ПРИМЕНЕНИЯ
GB0905641D0 (en) * 2009-04-01 2009-05-13 Serodus As Compounds
WO2021116487A1 (en) 2019-12-13 2021-06-17 Som Innovation Biotech, S.A. Compounds for use in the treatment of niemann-pick c disease
WO2025077825A1 (en) * 2023-10-13 2025-04-17 Fauna Bio Incorporated Methods and compositions for treating cardio-pulmonary disorders

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2557342A1 (de) * 1975-12-19 1977-06-30 Hoechst Ag Basisch substituierte indolderivate und verfahren zu ihrer herstellung
AU622330B2 (en) * 1989-06-23 1992-04-02 Takeda Chemical Industries Ltd. Condensed heterocyclic compounds having a nitrogen atom in the bridgehead for use as fungicides
CA2030051C (en) * 1989-11-17 2001-08-07 Haruhiko Kikuchi Indole derivatives
US5189041A (en) * 1990-11-16 1993-02-23 Syntex (U.S.A.) Inc. Tricyclic 5-ht3 receptor antagonists
GB9103862D0 (en) * 1991-02-25 1991-04-10 Glaxo Group Ltd Chemical compounds
US5206382A (en) * 1991-06-27 1993-04-27 Fidia Georgetown Institute For The Neurosciences Indole derivatives, pharmaceutical compositions and methods of treating neurological and psychiatric disorders

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8232285B2 (en) 2007-06-22 2012-07-31 Arqule, Inc. Quinazolinone compounds and methods of use thereof

Also Published As

Publication number Publication date
UA41311C2 (uk) 2001-09-17
HUT71121A (en) 1995-11-28
SI9300114B (sl) 2006-08-31
NO303638B1 (no) 1998-08-10
RU94040864A (ru) 1996-07-20
WO1993018036A1 (en) 1993-09-16
NZ249565A (en) 1997-07-27
NO943348L (no) 1994-11-09
GR3030668T3 (en) 1999-10-29
AP401A (en) 1995-08-29
EP0630376A1 (de) 1994-12-28
DE69333504D1 (de) 2004-06-09
ES2132223T3 (es) 1999-08-16
CZ286194B6 (cs) 2000-02-16
CN1085083A (zh) 1994-04-13
NO943348D0 (no) 1994-09-09
SG50693A1 (en) 1998-07-20
SI9300114A (sl) 1993-12-31
HU9402601D0 (en) 1994-12-28
DK0884319T3 (da) 2004-08-30
RU2104279C1 (ru) 1998-02-10
MY110110A (en) 1998-01-27
CY2510B1 (en) 2005-12-23
AP9300494A0 (en) 1993-04-30
JP2831467B2 (ja) 1998-12-02
DE69333504T2 (de) 2005-05-12
CA2131797A1 (en) 1993-09-16
MA22819A1 (fr) 1993-10-01
MX9301348A (es) 1993-09-01
HK1012352A1 (en) 1999-07-30
CZ221094A3 (en) 1995-09-13
CN1043893C (zh) 1999-06-30
CN1078471A (zh) 1993-11-17
ATE266033T1 (de) 2004-05-15
FI107158B (fi) 2001-06-15
ATE180785T1 (de) 1999-06-15
IL105003A0 (en) 1993-07-08
ES2219813T3 (es) 2004-12-01
DE69325167T2 (de) 2000-01-20
FI944204L (fi) 1994-09-12
HU219121B (hu) 2001-02-28
AU3644893A (en) 1993-10-05
FI944204A0 (fi) 1994-09-12
DK0630376T3 (da) 1999-06-23
KR950700304A (ko) 1995-01-16
EP0884319A3 (de) 1999-02-10
IL105003A (en) 1996-09-12
DE69325167D1 (de) 1999-07-08
EP0630376B1 (de) 1999-06-02
SK281423B6 (sk) 2001-03-12
KR100282730B1 (ko) 2001-02-15
JPH07504433A (ja) 1995-05-18
AU671102B2 (en) 1996-08-15
PT884319E (pt) 2004-09-30
EP0884319A2 (de) 1998-12-16
CA2131797C (en) 2010-05-18
SK107894A3 (en) 1995-04-12

Similar Documents

Publication Publication Date Title
EP0884319B1 (de) N- (1-nButyl-4-piperidyl)methyl -3,4-dihydro-2H- 1,3 oxazino 3,2-a indol-10-carboxamid oder ein pharmazeutisch annehmbares Salz davon
EP0604494B1 (de) 5-ht4 rezeptor antagonisten
AU2435092A (en) 5-ht4 receptor antagonists
US5620992A (en) Heteroaryl compounds used as pharmaceuticals
JPH08502274A (ja) ５−ｈｔ▲下４▼レセプターアンタゴニスト用イミダゾピリジン誘導体
US5852014A (en) Condensed indole derivatives as 5HT4 -receptor antagonists
EP0712406B1 (de) Kondensierte indol-derivate als 5-ht4-rezeptor-antagonisten
AP373A (en) Compounds having 5TH4 receptor antagonist activity.
EP0641198A1 (de) Arzneimittel zur behandlung von angstzuständen
HK1023560A1 (en) N-(1-nbutyl-4-piperidyl)methyl-3,4-dihydro-2h-1,3 oxazino 3,2-a indole-10-carboxamide or a pharmaceutically acceptable salt thereof
HK1023560B (en) N-(1-nbutyl-4-piperidyl)methyl-3,4-dihydro-2h-1,3 oxazino 3,2-a indole-10-carboxamide or a pharmaceutically acceptable salt thereof
RU2124512C1 (ru) Гетероциклическое соединение в качестве антагонистов 5-нт4 - рецепторов, способ получения и фармацевтическая композиция
AU668102C (en) 5-HT4 receptor antagonists
US20010031751A1 (en) Pharmaceuticals
HK1012352B (en) Condensed indole derivatives as 5-ht4-receptor antagonists
US20040176370A1 (en) 3,4-Dihdro-N-[[1-(3-hydroxybutyl)-4-piperidinyl]methyl]-2H-[1,3]oxazino[3,2-a]indole-10-carboxamide as 5-HT(4) receptor antagonist
HK1012347B (en) Condensed indole derivatives as 5-ht 4-receptor antagonists
WO2000017207A1 (en) 3,4-dihydro -n-[[1-(3 -hydroxybutyl) -4-piperidinyl] methyl] -2h-[1,3] oxazino[3, 2-a]indole -10-carboxamide as 5-ht(4) receptor antagonist
WO1999029697A1 (en) Pharmaceuticals

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19980729

AC Divisional application: reference to earlier application

Ref document number: 630376

Country of ref document: EP

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LI LU MC NL PT SE

PUAL Search report despatched

Free format text: ORIGINAL CODE: 0009013

AK Designated contracting states

Kind code of ref document: A3

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LI LU MC NL PT SE

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: SMITHKLINE BEECHAM PLC

GRAH Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOS IGRA

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

RIN1 Information on inventor provided before grant (corrected)

Inventor name: WYMAN, PAUL ADRIAN,GLAXOSMITHKLINE

Inventor name: GASTER, LARAMIE MARY,GLAXOSMITHKLINE

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AC Divisional application: reference to earlier application

Ref document number: 0630376

Country of ref document: EP

Kind code of ref document: P

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LI LU MC NL PT SE

RTI1 Title (correction)

Free format text: N- (1-NBUTYL-4-PIPERIDYL)METHYL -3,4-DIHYDRO-2H- 1,3 OXAZINO 3,2-A INDOLE-10-CARBOXAMIDE OR A PHARMACEUTICALLY ACCEPTABLE

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REF Corresponds to:

Ref document number: 69333504

Country of ref document: DE

Date of ref document: 20040609

Kind code of ref document: P

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: NV

Representative=s name: E. BLUM & CO. PATENTANWAELTE

REG Reference to a national code

Ref country code: GR

Ref legal event code: EP

Ref document number: 20040402165

Country of ref document: GR

REG Reference to a national code

Ref country code: SE

Ref legal event code: TRGR

REG Reference to a national code

Ref country code: DK

Ref legal event code: T3

REG Reference to a national code

Ref country code: PT

Ref legal event code: SC4A

Free format text: AVAILABILITY OF NATIONAL TRANSLATION

Effective date: 20040728

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2219813

Country of ref document: ES

Kind code of ref document: T3

ET Fr: translation filed
ET1 Fr: translation filed ** revision of the translation of the patent or the claims
REG Reference to a national code

Ref country code: HK

Ref legal event code: GR

Ref document number: 1023560

Country of ref document: HK

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20050208

REG Reference to a national code

Ref country code: CH

Ref legal event code: PFA

Owner name: SMITHKLINE BEECHAM PLC

Free format text: SMITHKLINE BEECHAM PLC#980 GREAT WEST ROAD#BRENTFORD, MIDDLESEX TW8 9GS (GB) -TRANSFER TO- SMITHKLINE BEECHAM PLC#980 GREAT WEST ROAD#BRENTFORD, MIDDLESEX TW8 9GS (GB)

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CH

Payment date: 20120126

Year of fee payment: 20

Ref country code: IE

Payment date: 20120228

Year of fee payment: 20

Ref country code: MC

Payment date: 20120228

Year of fee payment: 20

Ref country code: LU

Payment date: 20120316

Year of fee payment: 20

Ref country code: FR

Payment date: 20120328

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: PT

Payment date: 20120227

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: BE

Payment date: 20120328

Year of fee payment: 20

Ref country code: IT

Payment date: 20120321

Year of fee payment: 20

Ref country code: DK

Payment date: 20120227

Year of fee payment: 20

Ref country code: GB

Payment date: 20120227

Year of fee payment: 20

Ref country code: SE

Payment date: 20120307

Year of fee payment: 20

Ref country code: GR

Payment date: 20120228

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: NL

Payment date: 20120322

Year of fee payment: 20

Ref country code: DE

Payment date: 20120330

Year of fee payment: 20

REG Reference to a national code

Ref country code: DK

Ref legal event code: EUP

REG Reference to a national code

Ref country code: DE

Ref legal event code: R071

Ref document number: 69333504

Country of ref document: DE

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

REG Reference to a national code

Ref country code: PT

Ref legal event code: MM4A

Free format text: MAXIMUM VALIDITY LIMIT REACHED

Effective date: 20130310

REG Reference to a national code

Ref country code: NL

Ref legal event code: V4

Effective date: 20130310

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: AT

Payment date: 20120228

Year of fee payment: 20

BE20 Be: patent expired

Owner name: *SMITHKLINE BEECHAM P.L.C.

Effective date: 20130310

REG Reference to a national code

Ref country code: GB

Ref legal event code: PE20

Expiry date: 20130309

REG Reference to a national code

Ref country code: AT

Ref legal event code: MK07

Ref document number: 266033

Country of ref document: AT

Kind code of ref document: T

Effective date: 20130310

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20130309

Ref country code: DE

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20130312

REG Reference to a national code

Ref country code: SE

Ref legal event code: EUG

REG Reference to a national code

Ref country code: GR

Ref legal event code: MA

Ref document number: 20040402165

Country of ref document: GR

Effective date: 20130311

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PT

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20130319

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: ES

Payment date: 20120326

Year of fee payment: 20

REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20130806

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20130311

REG Reference to a national code

Ref country code: IE

Ref legal event code: MK9A

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IE

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20130310